Structure-Based Design of Y‑Shaped Covalent TEAD Inhibitors

Transcriptional
enhanced associate domain (TEAD) proteins together
with their transcriptional coactivator yes-associated protein (YAP)
and transcriptional coactivator with the PDZ-binding motif (TAZ) are
important transcription factors and cofactors that regulate gene expression
in the Hippo pathway. In mammals, the TEAD families have four homologues:
TEAD1 (TEF-1), TEAD2 (TEF-4), TEAD3 (TEF-5), and TEAD4 (TEF-3). Aberrant
expression and hyperactivation of TEAD/YAP signaling have been implicated
in a variety of malignancies. Recently, TEADs were recognized as being
palmitoylated in cells, and the lipophilic palmitate pocket has been
successfully targeted by both covalent and noncovalent ligands. In
this report, we present the medicinal chemistry effort to develop
MYF-03-176 (compound 22) as a selective, cysteine-covalent
TEAD inhibitor. MYF-03-176 (compound 22) significantly
inhibits TEAD-regulated gene expression and proliferation of the cell
lines with TEAD dependence including those derived from mesothelioma
and liposarcoma.

转录增强关联域（Transcriptional enhanced associate domain, TEAD）蛋白与其转录共激活因子Yes相关蛋白（yes-associated protein, YAP）以及含PDZ结合基序的转录共激活因子（transcriptional coactivator with PDZ-binding motif, TAZ）均为重要的转录因子及辅因子，在Hippo信号通路（Hippo pathway）中调控基因表达。在哺乳动物体内，TEAD家族包含4种同源蛋白：TEAD1（TEF-1）、TEAD2（TEF-4）、TEAD3（TEF-5）及TEAD4（TEF-3）。TEAD/YAP信号通路的异常表达与过度激活已被证实与多种恶性肿瘤相关。近期研究发现，TEAD蛋白可在细胞内发生棕榈酰化修饰，其亲脂性棕榈酸口袋已成功通过共价及非共价配体实现靶向结合。本研究报道了一项药物化学研发工作，成功开发出选择性半胱氨酸共价TEAD抑制剂MYF-03-176（化合物22）。该化合物可显著抑制TEAD调控的基因表达，以及依赖TEAD信号的细胞系（包括间皮瘤与脂肪肉瘤来源的细胞系）的增殖。